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A postzygotic GNA13 variant upregulates the RHOA/ROCK pathway and alters melanocyte function in a mosaic skin hypopigmentation syndrome

Author

Listed:
  • Rana El Masri

    (Institut Cochin
    University of Geneva)

  • Alberto Iannuzzo

    (Institut Cochin)

  • Paul Kuentz

    (FHU-TRANSLAD
    Centre Hospitalier Universitaire de Besançon)

  • Rachida Tacine

    (Institut Cochin)

  • Marie Vincent

    (CHU de Nantes - Hôpital Mère-Enfant)

  • Sébastien Barbarot

    (PhAN)

  • Fanny Morice-Picard

    (CHU de Bordeaux - GH Pellegrin)

  • Franck Boralevi

    (CHU de Bordeaux - GH Pellegrin)

  • Naia Oillarburu

    (CHU de Toulouse - Hôpital Larrey)

  • Juliette Mazereeuw-Hautier

    (CHU de Toulouse - Hôpital Larrey)

  • Yannis Duffourd

    (FHU-TRANSLAD
    FHU-TRANSLAD & Institut GIMI)

  • Laurence Faivre

    (FHU-TRANSLAD
    FHU-TRANSLAD & Institut GIMI)

  • Arthur Sorlin

    (FHU-TRANSLAD
    FHU-TRANSLAD & Institut GIMI
    1 Rue Louis Rech)

  • Pierre Vabres

    (FHU-TRANSLAD
    FHU-TRANSLAD & Institut GIMI
    Guy’s and St Thomas’ NHS Foundation Trust)

  • Jérôme Delon

    (Institut Cochin)

Abstract

The genetic bases of mosaic pigmentation disorders have increasingly been identified, but these conditions remain poorly characterised, and their pathophysiology is unclear. Here, we report in four unrelated patients that a recurrent postzygotic mutation in GNA13 is responsible for a recognizable syndrome with hypomelanosis of Ito associated with developmental anomalies. GNA13 encodes Gα13, a subunit of αβγ heterotrimeric G proteins coupled to specific transmembrane receptors known as G-protein coupled receptors. In-depth functional investigations revealed that this R200K mutation provides a gain of function to Gα13. Mechanistically, we show that this variant hyperactivates the RHOA/ROCK signalling pathway that consequently increases actin polymerisation and myosin light chains phosphorylation, and promotes melanocytes rounding. Our results also indicate that R200K Gα13 hyperactivates the YAP signalling pathway. All these changes appear to affect cell migration and adhesion but not the proliferation. Our results suggest that hypopigmentation can result from a defect in melanosome transfer to keratinocytes due to cell shape alterations. These findings highlight the interaction between heterotrimeric G proteins and the RHOA pathway, and their role in melanocyte function.

Suggested Citation

  • Rana El Masri & Alberto Iannuzzo & Paul Kuentz & Rachida Tacine & Marie Vincent & Sébastien Barbarot & Fanny Morice-Picard & Franck Boralevi & Naia Oillarburu & Juliette Mazereeuw-Hautier & Yannis Duf, 2025. "A postzygotic GNA13 variant upregulates the RHOA/ROCK pathway and alters melanocyte function in a mosaic skin hypopigmentation syndrome," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56995-4
    DOI: 10.1038/s41467-025-56995-4
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    References listed on IDEAS

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    1. Catherine D. Van Raamsdonk & Vladimir Bezrookove & Gary Green & Jürgen Bauer & Lona Gaugler & Joan M. O’Brien & Elizabeth M. Simpson & Gregory S. Barsh & Boris C. Bastian, 2009. "Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi," Nature, Nature, vol. 457(7229), pages 599-602, January.
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